Tu Chia-Ling, Chang Wenhan, Sosa Julie A, Koh James
Endocrine Research Unit, Department of Medicine, San Francisco Department of Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94158.
Endocrine Neoplasia Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA 94143.
PNAS Nexus. 2023 Mar 9;2(3):pgad073. doi: 10.1093/pnasnexus/pgad073. eCollection 2023 Mar.
Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population (1-3), but the basis for this association remains unclear. We employed a spatially defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from vitamin D-deficient or vitamin D-replete PHPT patients. A cross-sectional panel of eucalcemic cadaveric donor parathyroid glands was examined in parallel as normal tissue controls. Here, we report that parathyroid tumors from vitamin D-deficient PHPT patients (Def-Ts) are intrinsically different from those of vitamin D-replete patients (Rep-Ts) of similar age and preoperative clinical presentation. The parathyroid oxyphil cell content is markedly higher in Def-Ts (47.8%) relative to Rep-Ts (17.8%) and normal donor glands (7.7%). Vitamin D deficiency is associated with increased expression of electron transport chain and oxidative phosphorylation pathway components. Parathyroid oxyphil cells, while morphologically distinct, are comparable to chief cells at the transcriptional level, and vitamin D deficiency affects the transcriptional profiles of both cell types in a similar manner. These data suggest that oxyphil cells are derived from chief cells and imply that their increased abundance may be induced by low vitamin D status. Gene set enrichment analysis reveals that pathways altered in Def-Ts are distinct from Rep-Ts, suggesting alternative tumor etiologies in these groups. Increased oxyphil content may thus be a morphological indicator of tumor-predisposing cellular stress.
原发性甲状旁腺功能亢进症（PHPT）是一种常见的内分泌肿瘤性疾病，其特征是由于甲状旁腺激素（PTH）分泌异常升高导致钙稳态失调。与普通人群相比，PHPT患者血清25-羟基维生素D（25OHD）水平低的情况更为普遍（1-3），但这种关联的基础尚不清楚。我们采用空间定义的原位全转录组学和选择性蛋白质组学分析方法，比较维生素D缺乏或维生素D充足的PHPT患者甲状旁腺腺瘤中的基因表达模式和细胞组成。同时，对一组血钙正常的尸体供体甲状旁腺进行横断面检查，作为正常组织对照。在此，我们报告，维生素D缺乏的PHPT患者（Def-Ts）的甲状旁腺肿瘤与年龄和术前临床表现相似的维生素D充足患者（Rep-Ts）的甲状旁腺肿瘤本质上不同。Def-Ts中甲状旁腺嗜酸性细胞含量（47.8%）明显高于Rep-Ts（17.8%）和正常供体腺体（7.7%）。维生素D缺乏与电子传递链和氧化磷酸化途径成分的表达增加有关。甲状旁腺嗜酸性细胞虽然形态不同，但在转录水平上与主细胞相当，维生素D缺乏以类似方式影响这两种细胞类型的转录谱。这些数据表明嗜酸性细胞来源于主细胞，并暗示其丰度增加可能是由低维生素D状态诱导的。基因集富集分析表明，Def-Ts中改变的途径与Rep-Ts不同，提示这些组中存在不同的肿瘤病因。因此，嗜酸性细胞含量增加可能是肿瘤易感性细胞应激的形态学指标。
